Patients with a variety of disorders receive intermittent or chronic transfusion support or require tissue grafting to replace a defective organ. For individuals requiring transfusion support, they have either a genetic or acquired deficiency of one or more blood components that require replacement therapy. Many different products prepared from blood are available for transfusion, including both cellular and plasma components. However, repeated exposure to blood products often results in recipient recognition of the foreign transfused antigens. Such immune recognition of the foreign antigens results in a failure to achieve a benefit from the transfusion and in some circumstances may even cause a transfusion reaction with adverse consequences to the recipient.
Several approaches have been used to either prevent or delay alloimmunization. The majority of the techniques involve giving immunosuppressive therapy to the transfusion recipient to prevent recognition of the transfused foreign antigens. Such immunosuppressive therapy is often inadequate to suppress the recognition process resulting in alloimmunization in spite of the treatment. Furthermore, the immunosuppressive therapy may have undesirable side effects including organ toxicity and immunosuppression of desirable responses such as recognition and destruction of pathogenic bacteria.
Once an immune response to foreign antigens has occurred, there is little evidence that any immunosuppressive therapy is beneficial. Continued adequate transfusion support is possible only if antigen matching between donor and recipient is achieved. Often a matched donor is not available or for some transfusion products so little is known about the antigen systems involved in the immune response that laboratory methods are not available to appropriately select a matched donor.
An alternative approach to preventing alloimmunization, other than immunosuppressing the recipient, is to reduce the immunogenicity of the transfused product. As al transfused blood products are immunogenic and will eventually induce an immune response in most transfused recipients, any procedure that can prevent or at least delay immunization is beneficial. Selecting only antigen compatible donors beginning with the first transfusion is possible in some circumstances but for the majority of patients not enough donors are available to continue this process or a matching procedure does not exist.
For organ grafting, because there is persistent exposure to foreign tissue antigens, eventual rejection of the grafted tissue occurs. To prevent graft rejection several approaches have been used: recipient immunosuppression, matching tissue antigens of donor and recipient, reducing the immunogenicity of the grafted tissue, or inducing a state of tolerance in the recipient to the foreign antigens of the graft. Furthermore, depending on the tissue being grafted different approaches may be required to achieve a successful graft and combined therapies may be additive in their beneficial effects. For example, in bone marrow transplantation massive doses of chemo-radiotherapy are given to the recipient to destroy the recipient's autologous marrow and to induce immunosuppression to allow engraftment of the donor marrow. Even better results are obtained if marrow donor and recipient are related and well-matched for the major histocompatibility antigen system (HLA). Although post-marrow grafting immunosuppression is usually given, it is for only a limited time.
In contrast, for kidney grafting lesser degrees of immunosuppressive therapy are required to avoid unacceptable marrow and gastrointestinal toxicity. Furthermore, continuous post-grafting immunosuppression is required. Often a related kidney donor is not available, and lesser degrees of HLA matching between donor and recipient are more often accepted than for bone marrow transplantation.
Another major difference between these two types of tissue grafting are the effects of prior transfusions on engraftment. For kidney graft recipients, prior transfusions, particularly from the intended kidney donor, are beneficial apparently by inducing some degree of tolerance to the subsequent kidney graft. However, prior blood transfusions before marrow grafting, especially if the blood has come from the intended marrow donor, markedly increases the risk of graft rejection. Thus, although there are similarities in procedures to enhance organ grafts (immunosuppression and donor-recipient HLA matching) there are clear differences in (1) the amounts, type, and duration of immunosuppression required; (2) the acceptance of non-HLA identity between organ donor and recipient; and, (3) the effects of prior transfusions on enhancing or impairing a subsequent organ graft. Furthermore, even the best combined therapies are not always successful in ensuring a successful organ graft, and there may be substantial toxicities associated with the therapies being used.
Besides using HLA matching and recipient immunosuppression, efforts to directly reduce immunogenicity of the engrafted tissue or to enduce tolerance in the recipient, other than by prior blood transfusions in kidney recipients, have been limited. In bone marrow transplantation efforts to purify or enrich the marrow graft for stem cells and eliminate T-lymphocytes that may be responsible for graft vs. host disease (a post-grafting complication) have often resulted in a transplanted marrow that has failed to engraft. Some investigators have stored r cultured the graft in vitro prior to transplantation (skin grafting) to facilitate engraftment. Most of these latter methods to enhance organ grafting have had limited success.
It would be advantageous to avoid immune recognition by the recipient of incompatible donor antigens and the consequent destruction of allogeneic tissue following transfusion or transplantation.